Ashok E. Philip, Jacques H. Poupaert, Gwénaël Chevé, Giulio Muccioli, Didier Lambert, Christopher R. McCurdy

Structure–activity relationship of phenytoinergic antiepileptic drugs related to ameltolide

Med Chem Res (2007) 16:130–135

Abstract Ameltolide shares with phenytoin and carbamazepine a common mode of action involving interaction with central voltage-dependent sodium channels.
Ameltolide and structurally related benzanilides were subjected to molecular modeling studies using both molecular mechanics (MM2, Amber96, and OPLS) and
semiempirical quantum mechanics (AM1, PM3, and PM3 Cosmo) to resolve a paradox: while compounds with a phenytoin-like pharmacological profile possess a
CO-NH moiety in a cis-configuration, ameltolide was found via X-ray crystallography to exist in the trans-configuration. Results obtained both by molecular
mechanics and semiempirical methods indicate that for ameltolide, the cis and trans forms have similar energy content. Additional ab initio calculations performed at 6–
31G** gave a DE (Z – E) on the order of 3 kcal/mol. In view of this small energy difference between the cis and trans forms, it is conceivable that these benzanilides
bind to their biological target in their cis configuration, therefore assuming a common structure–activity relationship with classical antiepileptic agents.